Xenobiotic Metabolism and Detoxification

• Xenobiotics, from the Greek words "xenos" (strange) and "foreign", are compounds introduced to the body, such as drugs, industrial chemical carcinogens, artificial sweeteners, alcohol, and cosmetics.
• A vast majority of foreign compounds are toxic and should be quickly eliminated to detoxify the body from unwanted substances.
• Detoxification or detoxication is defined as the series of biochemical reactions converting foreign compounds to non-toxic or less toxic, more easily excretable forms.
• Detoxification involves 2 phases

Xenobiotic Metabolism

• The aim is to make agents less or non-toxic and to make them soluble compounds easily excreted in urine
• The liver is the main organ involved and is equipped with the enzyme machinery
• Kidneys and other organs may also be involved
• Detoxification products are mostly excreted by kidneys, and less frequently via feces or expired air

Mechanism of Detoxification

• Xenobiotic metabolism can be divided into two phases that may occur together or separately.
• Phase I reactions are oxidation, reduction, and hydrolysis.
• Phase II reactions are conjugation reactions, involving compounds such as glucuronic acids, amino acids (glycine), glutathione, sulfate, acetate, and methyl groups.
• Phase I and II reactions are generally involved in the detoxification of a compound
• In xenobiotic metabolism, oxidation followed by conjugation is the most frequent process.

Reactions of Phase I

• Occurs in the liver
• Needs cytochrome P450
• Oxidation of ethanol to acetic acid serves as an example

Cytochrome P450

• Typically a Mono-oxygenase
• Incorporates one atom of oxygen to form hydroxy-derivatives while the second atom of oxygen is reduced to water.
• Requires O2 and NADPH++H as a coenzyme

Detoxification by Hydrolysis

• Occurs in the liver
• The toxicity of some drugs can be eliminated via hydrolysis
• Aspirin (acetyl salicylic acid) converting to salicylic acid + acetic acid serves as an example

Detoxification by Reduction

• Examples include
• Picric acid converting to Picramic acid
• Chloral converting to Trichloroethanol
• Nitrobenzene converting to Aminobenzene

Reactions of Phase II

• Occurs by conjugation
• A foreign compound combines with a substance produced in the body.
• May occur either directly or after the phase I reactions
• At least 8 conjugating agents identified
• These are glucuronic acid, glycine, cysteine (of glutathione), glutamine, methyl group, sulfate, acetic acid and thiosulfate

Drug-Drug or Drug-Food interactions relative to CYP activity

• A number of CYP isoenzymes are expressed in mammalian species, including humans
• Many of these isoenzymes play a role with anabolic steroids and are localized in the liver
• The pedigree is indicated by an Arabic numeral (family), a capital letter (subfamily) and another Arabic numeral (gene), e.g. CYP1A2
• Enzymes transforming drugs in humans belong to the CYP families 1-4
• Thirty human CYP isozymes have been identified
• 90% of human drug oxidation can be attributed to six main enzymes: CYP1A2, 2C9, 2C19, 2D6, 2E1 and 3A4/5
• Drugs interact with the CYP450 system in several ways
• Drugs may be metabolized by only one CYP450 enzyme (e.g., metoprolol by CYP2D6) or by multiple enzymes (e.g., warfarin by CYP1A2, CYP2D6, and CYP3A4)
• Drugs that cause CYP450 metabolic drug interactions are referred to as either inhibitors or inducers
• Inhibitors block the metabolic activity of one or more CYP450 enzymes while inducers increase CYP450 enzyme activity by increasing enzyme synthesis.
• Physicians should exercise caution when prescribing a drug known to be a CYP450 inhibitor or inducer because the target drug may need to be substituted or the dose adjusted to account for a potential decrease or increase in metabolism.
• Information regarding a drug's CYP450 metabolism and its potential for inhibition or induction can be found on the drug label and accessed through the U.S. Food and Drug Administration (FDA) or manufacturer's Web sites

CYP450 & Drug-Drug Interactions

• Amiodarone is an effective drug in controlling supraventricular and ventricular arrhythmias, and is used when other drugs have failed.
• Using amiodarone for patients with cardiac disease in therapeutic combination with coumadin derivatives (e.g., Warfarin) prescribed for thromboembolic prophylaxis.
• Amiodarone seems to augment the anticoagulant effects of warfarin by lowering vitamin K-dependent coagulation factors.
• Adjustment of the warfarin dosage is a better solution for managing the interaction, instead of altering the amiodarone dosage or drug cessation.
• Diltiazem is a calcium channel blocker which works by affecting the movement of calcium into heart and blood vessels, relaxing blood vessels, lowering blood pressure, and increasing oxygen and blood supply to the heart while reducing its workload.
• Prednisone is a corticosteroid used to treat allergies, blood disorders, skin diseases, inflammation, infections and certain cancers, and prevent organ rejection after a transplant.
• Diltiazem & Prednisone are used greatly in renal transplantation.
• Diltiazem and prednisone can enhance immunologic and other clinical effects, thereby causing immunosuppression, due to increased prednisolone serum levels

CYP450 & Drug-Food Interactions

• Many drugs need CYP3A4 to be broken down (metabolized) with the help of a vital enzyme in the small intestine
• Grapefruit juice may block intestinal CYP3A4, causing more of the drug to enter the blood and stays in the body longer, leading to too much drug
• The CYP3A4 enzyme in the intestine varies in amount from person to person, so grapefruit juice affects people differently even when they take the same drug
• Grapefruit juice can have the opposite effect on other drugs, like fexofenadine (Allegra).
• Grapefruit juice can affect proteins in the body known as drug transporters, and drug transporters help move a drug into cells for absorption, which leads to less of the drug entering the blood to be as effective
• You should ask your doctor or pharmacist if grapefruit juice interacts with your medication
• Read the medication guide or patient information sheet to learn about grapefruit juice affecting your drug
• Read the Drug Facts label on your OTC (Over-the-counter) drug to avoid grapefruit or other fruit juices
• If you must avoid grapefruit juice with your medicine, check the labels of fruit juices or drinks flavored with fruit juice to see whether they are made with grapefruit juice.
• Seville oranges (often used to make orange marmalade), pomelos, and tangelos might have the same effect as grapefruit juice, so avoid eating these foods.